rev bras hematol hemoter. 2016;38(4):279–280
w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Scientific
Comment
New
developments
in
the
understanding
and
diagnosis
of
myelodysplastic
syndromes
with
ring
sideroblasts
夽
Lorena
Bedotti
Ribeiro,
Erich
V.
De
Paula
∗UniversidadedeCampinas(Unicamp),Campinas,SP,Brazil
Myelodysplasticsyndromes(MDS)representagroupofclonal hematopoietic stem cell disorders in which cytopenias of variable severity are associated withdysplastic changes of hematopoieticprecursors,andahigherriskofprogressionto acutemyeloidleukemia(AML).1Besidesdysplasia,the
pres-enceofringsideroblasts(RS)haslongbeenrecognizedasan importantmorphologicfeatureofMDS;itusedtodefinea sub-setofpatientswithinthisgroup.Accordingly,theWorldHealth Organization(WHO)criteriarevisedin2008definedrefractory anemiawithringsideroblasts(RA-SR)asaspecificMDS sub-group,morphologicallycharacterizedbyerythroid dysplasia andthepresenceofatleast15%RSinbonemarrowsmears.2
However,seminal studies publishedwithin the lastfive years havechanged concepts and diagnostic definitions in thefieldofmyeloidmalignanciesswiftly.Amongthese stud-ies,made possiblebythe developmentofhigh-throughput sequencingtechnologies,thedescriptionofmutations associ-atedwithMDSandAMLinlargepatientcohorts,3–5followed
bythedemonstrationthatsomeofthesemutationsarealso present (though with a lower allele burden)in individuals withoutevidenthematologicalterations,6–8ledtotheproposal
ofanewpathologicalcategorytermedclonalhematopoiesis ofindeterminatepotential(CHIP).9Thiscouldbeconceptually
viewed for myeloid neoplasms, as monoclonal gammopa-thy ofundetermined significanceis formultiplemyeloma.
DOIoforiginalarticle:http://dx.doi.org/10.1016/j.bjhh.2016.06.002.
夽
SeepaperbyDonairesetal.inRevBrasHematolHemoter.2016;38(4):320–324.
∗ Correspondingauthorat:FacultyofMedicalSciences,UniversityofCampinas,RuaTessáliaVieiradeCamargo,126,CidadeUniversitária
ZeferinoVaz,13083-887Campinas,SP,Brazil. E-mailaddress:erich@unicamp.br(E.V.DePaula).
Furthermore–asexploredinastudy inthisedition ofthe Revista Brasileira de Hematologia e Hemoterapia (RBHH)10
– thesestudies alsoresulted inthe description ofthe first associationbetweenanacquiredmutationandaspecific mor-phologicabnormalityofhematopoieticprecursorsinMDS.
High-throughput whole genome sequencing studies revealed that mutationsin genes involvedin RNAsplicing are foundin ∼45–85% ofpatients with MDS. In particular, somaticmutationsofsplicingfactor3bsubunit1(SF3B1)have been identified in ∼60–80% of MDS-RS patients4,5 with an
extremely high predictive value for the disease phenotype withRS,asSF3B1isemergingasthefirstgenetobestrongly associated witha specificmorphological feature ofMDS.11
Moreover,MDSpatientscarryingSF3B1mutationspresenta fairlyhomogeneousdiseasephenotypeoftencharacterizedby isolated erythroiddysplasia, significanterythroid dysplasia, and high proportion of RS. Even more importantly, these patients presentsignificantlybettersurvivalandlower risk ofprogressiontoAML.11,12 Together,thesedatasupporteda
significantchangeintherevisedWHOclassificationofMDS in2016,whichestablishedthat, inthepresenceofaSF3B1 mutation,adiagnosisofMDS-RSmaybedefinedwithRSin as fewas 5%ofnucleatederythroid cells,with the former threshold of 15% RS reserved for cases lacking a demon-strable SF3B1 mutation.13 These patients will be classified
http://dx.doi.org/10.1016/j.bjhh.2016.08.003
280
revbrashematolhemoter.2016;38(4):279–280as‘MDSwithsinglelineagedysplasiaand ringsideroblasts (MDS-RSSLD)’or‘MDSwithmultilineagedysplasiaandring sideroblasts(MDS-RSMLD)’.13
ItisinthischangingcontextthatDonairesetal.present astudyinwhichSF3B1mutationswerescreenedin91MDS patientsfromtwodistinctgeographicalareasofBrazil,usinga strategytargetingthemostfrequentlymutatedexonsofSF3B1 bydirectSangersequencing.10 Intotal, 7%ofpatients
pre-sentedheterozygousSF3B1 mutations,all ofthem withRS. TheproportionofpatientspresentingSF3B1mutationswas somewhatlowerthanreportedinEuropeandNorthAmerica, afindingthattheauthorsspeculatetobeassociatedwiththe heterogeneousbackgroundoftheBrazilianpopulation,orto thefactthat onlymutationhotspotswereevaluatedinthe SF3B1geneusingtheirscreeningstrategy.Theauthors also provideadetailedreviewofthecellularandmolecular mech-anismsbywhichSF3B1mutationsleadtoRS,andaninsilico simulation ofthe putative consequences ofeach mutation thattheyfoundinthefunctionofSF3B1protein.
Thequickimpactoftheidentification oftheassociation ofSF3B1 mutationswithRS on classicaldiagnostic criteria forMDSillustratehowfastnewmolecular biologyfindings caninfluencethepracticeofthegeneralhematologist. Well-knownchallengesinthedifferentialdiagnosisofMDS,14and
the prospects that new molecular data also pave the way toimproveriskstratificationandtreatmentstrategies15
cor-roboratetheimportanceofstudiesaddressingthemolecular pathogenesisof myeloid malignancies and in particularof MDS.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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